Pain and visceral hypersensitivity are the main characteristics of irritable bowel syndrome (IBS), an extremely common disorder affecting up to 15% of the US population with a major socioeconomic impact, while presenting one of the most vexing clinical challenges to physicians who treat it. Women are affected about twice as often as men; however the physiological basis of this sexual dimorphism remains elusive. A central concept to the mechanisms of chronic visceral hypersensitivity is the development of hyperexcitability of neurons in the spinal cord gray matter, which can evolve in response to peripheral tissue irritation. We have shown earlier that acute and inflammatory visceral pain is processed in the central nervous system (CNS) by a relatively specific visceral pain pathway formed by the axons of postsynaptic dorsal column (PSDC) neurons that ascend in the dorsal column (DC) to the dorsal column nuclei (DCN). In addition, we have shown that persistent abdominal pain without inflammation can be modeled in animals. Colon irritation (CI) in neonate but not adult rats, can cause a long lasting visceral hypersensitivity that persists after the initial injury has resolved and in the absence of identifiable pathology. This hypersensitivity is observed to variable extents in male and female rats. Therefore, in this study, we propose to study the hormonal basis of the sexual dimorphism observed in chronic visceral hypersensitivity as well as its underlying physiological mechanisms. The central hypothesis is that sex hormones play a crucial role in the sex-specific differences in visceral pain possibly via their action on pain pathways in the central nervous system. Sex hormones modulate i) visceral sensitivity, and ii) central neural sensitization, iii) via direct action on estrogen receptors located on PSDC neurons or iv) via regulation of glutamate receptors located on these neurons. Defining the physiological and cellular mechanisms that contribute to persistent visceral hypersensitivity, including the role of sex hormones, is of central importance to advancing our understanding of visceral pain in general, and functional abdominal pain in particular, and to foster a new approach to pain in gastrointestinal disorders that leads to the development of new, gender-sensitive, therapeutic tools for the management of chronic visceral pain. Public Health Relevance: In this study, we propose to study the hormonal basis of the sexual dimorphism observed in chronic visceral hypersensitivity as well as its underlying physiological mechanisms. The central hypothesis is that sex hormones play a crucial role in the sex-specific differences in visceral pain possibly via their action on pain pathways in the central nervous system. Sex hormones modulate i) visceral sensitivity, and ii) central neural sensitization, iii) via direct action on estrogen receptors located on postsynaptic dorsal column (PSDC) neurons or iv) via regulation of glutamate receptors located on these neurons. Defining the physiological and cellular mechanisms that contribute to persistent visceral hypersensitivity, including the role of sex hormones, is of central importance to advancing our understanding of visceral pain in general, and functional abdominal pain in particular, and to foster a new approach to pain in gastrointestinal disorders that leads to the development of new, gender-sensitive, therapeutic tools for the management of chronic visceral pain.